The role of macrophage-myofibroblast transition in the pathogenesis of multi-organ fibrosis.

Fibrotic repair is an innate protective mechanism activated following tissue injuries to promote structural stability and adaptability. However, when this process persists beyond appropriate temporal and spatial limits, it becomes pathological, culminating in irreversible cellular damage and organ dysfunction-similar to a sponge losing its flexibility due to excessive adhesions. These pathological alterations fundamentally rely on myofibroblast-mediated intercellular transition and the accumulation of extracellular matrix (ECM). Increasing evidence indicates that myofibroblasts can originate from multiple cellular sources, with macrophage-myofibroblast transition (MMT) as a key factor. MMT significantly impacts fibrotic processes in the liver, heart, kidneys, and lungs, with emerging evidence in skeletal muscle, involving several molecular signaling pathways including TGF-β/Smad3, ALKBH5/IL-11, Src kinase, and Jmjd3/IRF4 axes. Organ-specific molecular pathways provide precision therapeutic targets for clinical intervention. This review consolidates current findings into the mechanistic roles of MMT in the progression of fibrosis across different organs, highlighting that therapeutically targeting MMT represents a promising strategy for reversing fibrosis and restoring the function of affected organs.